| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults with Warm Autoimmune Hemolytic Anemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Autoimmune Hemolytic Anemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002285 |
| E.1.2 | Term | Anemia hemolytic autoimmune (NOS) |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of nipocalimab in participants with warm autoimmune hemolytic anemia (wAIHA). |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of this study are to evaluate the:
- Impact of nipocalimab treatment on fatigue
- Impact of nipocalimab on corticosteroid use
Other secondary objectives of this study are to evaluate the:
- Effects of nipocalimab on normalization of hemolytic markers
- Effects of nipocalimab on maintaining response in Hgb
-Effects of nipocalimab on normalization of hematologic and hemolytic parameters
-Effects of nipocalimab on the time to, and the duration of, Hgb response
- Impact of nipocalimab treatment on fatigue improvement
-Effects of nipocalimab on health-related quality of life and health status
-Association between IgG reduction and Hgb/hemolysis parameters
- Impact of nipocalimab on the reduction of corticosteroid dose |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Double blind period
1.Male or female ≥18 years of age.
2.Diagnosed with active primary or secondary wAIHA, defined as:
a.Hgb value <10 g/dL AND
b.Signs of hemolysis, defined as: lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN), or haptoglobin below the lower limit of normal, or indirect bilirubin above the ULN AND
c.Serological evidence of anti-erythrocyte antibodies assoc. with a DAT that is either positive for IgG only or is positive for IgG and C3d at screening. DAT: negative, can be repeated once. If neg., participants not eligible.
3.Diagnosed with wAIHA for at least 3 months, and currently receiving or has previously received treatment for wAIHA (treatment naive participants not eligible)
4.If on corticosteroids, participants must have been on treatment for at least 4 weeks with a stable dose during screening or for at least 14d prior to randomization, whichever is longer. Note: Investigators can optimize the above background medications prior to randomization if they are following the above rules for stable dose duration.
5. If receiving immunosuppressants, following drugs allowed: are azathioprine, mycophenolate mofetil/mycophenolic acid, methotrexate, cyclosporine, tacrolimus, danazol, and cyclophosphamide. Participants on stable dose of these drugs for ≥12weeks prior screening and during the screening period. If stopped, for at least 8 weeks prior to screening. Note: Investigators can optimize the above background medications prior to randomization if they are following the above rules for stable dose duration.
6. Have a platelet count ≥30 × 109/L.
7. Participants who have undergone splenectomy must be at least 3 mths post resection prior to screening and must be vaccinated as per the US Center for Disease Control and Prevention (CDC) annual Recommended Immunization Schedule for Adults Aged 19 Years or Older, US
8. Participants with other autoimmune disease or lymphoproliferative
disorders may be eligible if they are stable (no changes in concom. disease-related medications and severity of disease for at least 3 months prior to screening). Participants with lymphoproliferative disease must have a low grade, be stable and be unlikely to require chemotherapy or monoclonal antibody therapy during the double blind period of the study. Participants requiring change of treatment or new treatment for autoimmune or lymphoproliferative diseases (but not rescue therapy for wAIHA)during the DBP will be terminated from the study
9. Have sufficient venous access to allow drug administration by IV
infusion and blood sampling as per the protocol.
10. Women of childbearing potential, defined as physiologically capable of becoming pregnant, must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Baseline.Menopausal women must have an elevated serum FSH level at Screening; if the FSH is not elevated,they are considered to be of childbearing potential and must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Baseline to be eligible.
11. Women of childbearing potential (incl. menopausal who do not have elevated FSH) must agree to remain totally abstinent or to consistently use a reliable and highly effective method of contraception during the study and for 30 days after the last dose of study drug.
12. Male participants must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for at least 90 days after receiving the last dose of study drug. In addition, male participants with partners who are a woman of childbearing potential are to be highly encouraged to inform their partner to use highly effective contraception methods that result in a low failure rate (less than 1% per year)
13. Participants who use herbal,naturopathic,traditional Chinese
remedies,ayurvedic and nutritional supplements,or medical marijuana (with a doctor's prescription) are eligible if the use of these medications is acceptable to the Investigator.These remedies must be at a stable dose and regimen using the same preparation for ≥2months prior to Screening.
14. Able to understand and voluntarily provide written informed
consent to participate in the study and comply with all study procedures.Patients who initially provide consent and subsequently withdraw it prior to randomization,will be deemed as having failed this inclusion criterion.
15. Vaccinations prior to screening as per routine local guidelines
(including COVID-19).
Open-Label
1.Have completed the DBP (through Week 24),or have required rescue therapy at/or after Week 4 of the double-blind period, or failed to demonstrate an increase from baseline in Hgb of at least 1g/dL and are symptomatic at or after Week 16 of the double-blind period.
2.Are able to understand and voluntarily provide written informed consent to participate in the OLE period and comply with all study procedures.
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| E.4 | Principal exclusion criteria |
Double blind period
1. Are currently taking IgG Fc-related protein therapeutics.
2.Have received transfusion within 30 days prior to randomization.
3.Have any other associated cause of hereditary or acquired hemolytic anemia.
4.Have received rituximab within 3 months prior to screening.
5.Have received IVIg within 6 weeks prior to screening.
6.Have been diagnosed with cold antibody AIHA, cold agglutinin syndrome, mixed type (ie, warm and cold) AIHA, or paroxysmal cold hemoglobinuria. 7.Have a severe infection that requires parenteral anti-infectives and/or hospitalization, and/or is assessed as serious/clinically significant by the Investigator, within 8 weeks prior to screening. Any participant with an infection requiring oral antiinfectives within 4 weeks prior to screening will be excluded.
8.Have a chronic infection or require chronic treatment with anti- infectives.
9.Have received a live viral or bacterial vaccine within 4 weeks prior to first dose of study drug, or have a known need to receive a live viral or bacterial vaccine during the study or within at least 8 weeks after the last dose of study drug. For information regarding the Bacille CalmetteGuérin (BCG) vaccine, please see Exclusion Criterion 25.
10. Have any confirmed or suspected clinical immunodeficiency syndrome not related to treatment of their wAIHA, or has a family history of congenital or hereditary immunodeficiency unless confirmed absent in the participant.
11. Have any of the following viral testing outcomes: A history of HIV infection or positive test result for HIV-1 and HIV 2 antibodies; positive test for hepatitis B virus surface antigen. For participants with a negative test for HBsAg along with a positive test for anti-hepatitis B core antibodies and a positive or negative test for anti-HBs antibodies, hepatitis B viral DNA detection will be performed. Participants with a positive hepatitis B viral DNA detection will be excluded. If HBV DNA testing cannot be performed, or there is evidence of chronic liver disease, the participant is not eligible for the protocol; A positive test for hepatitis C virus (HCV) unless 1 of the following conditions are met: (a) Has a history of successful treatment, defined as being negative for HCV RNA at least 24 weeks after completing antiviral treatment, and has a negative HCV RNA test result at screening, OR (b) -Has a negative HCV RNA test result at least 24 weeks prior to screening and a negative HCV RNA test at the screening.
12. Are currently breastfeeding, pregnant, intend to become pregnant during the study, or are planning egg donation during the study or within 30 days after the last dose of study drug.
13. Have current alcohol/substance abuse/dependence, a history of alcohol/substance abuse/dependence within the 12 months prior to screening, or, in the Investigator's opinion, show evidence of ongoing alcohol/substance abuse/dependence.
14. Are currently participating in another interventional clinical trial or have received any investigational drug within the past 3 months prior to screening.
15. Have had any major surgery within 3 months prior to screening or have plans for or have been scheduled for any elective surgery or major dental procedure during the study.
16. Have a history of a major organ transplant, or hematopoietic stem cell/marrow transplant.
Further exclusion criteria listed in the protocol not listed here due to character restriction.
Open Label Extension
1. Met any of the stopping criteria or discontinued study drug during the double-blind period due to treatment-related AE.
2. Currently have a serious or clinically significant infection requiring parenteral anti-infectives and/or hospitalization. The following exclusion criterion from the Double-blind Period also applies to enrollment in the OLE: Exclusion Criteria #8 and #21. Exception: Participants who were previously enrolled in this study and unable to complete the double-blind period due to the Sponsor suspending dosing due to the COVID-19 pandemic can be enrolled in the OLE after meeting all of the double-blind eligibility criteria. Participants who completed the 28-week OLE before Amendment 6 can be re-enrolled in the OLE per investigator's discretion if the participants continue meet the eligibility criteria for the OLE. Participants will resume study treatment calculated from the baseline visit once they have reconsented to the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is durable response in improvement of Hgb, defined as the attainment of the following at 3 consecutive visits (minimum duration 28 days), where at least the first is at or before Week 16, without the need of rescue therapy:
• Hgb concentration ≥10 g/dL AND
• An increase from baseline in Hgb ≥2 g/dL The first of the three consecutive visits must be at or before week 16 of the double-blind period in order to qualify for success in the primary efficacy endpoint. For example, if a participant attained the above criteria at weeks 18, 20, and 22 and not before, this participant would not be considered a success. If the participant attained the criteria at weeks 16, 18, and 20, the patient would be considered a success.
Participants who took rescue therapy before reaching the criteria will be treated as having failed the primary efficacy outcome. If a participant has missing Hgb at both screening and baseline but is randomized by mistake, the participant will be excluded from the ITT analysis. This situation is unlikely to happen because the IVRS system requires screening Hgb for randomization to occur. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first of the three consecutive visits must be at or before week 16 in order to qualify for success in the primary efficacy endpoint. |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
-Change in the level of participant fatigue. Change from baseline in the total score from the FACIT-Fatigue Scale at the time of durable response.
-Change from baseline in the total score from the FACIT-Fatigue Scale at the end of the double-blind period (Week 24)
-Percent reduction from baseline in average daily dose of prednisone or equivalent at Week 24 of the double-blind period among participants on prednisone or equivalent at baseline. Other Secondary Endpoints:
-Normalization of hemolytic markers
1. Proportion of participants who simultaneously attain normal lactate dehydrogenase (LDH), AND normal haptoglobin, AND normal indirect bilirubin levels at 3 consecutive visits
2. Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH, and haptoglobin, and indirect bilirubin levels at any time during the study
3. Attainment of a 2 g/dL Hgb increase from baseline AND normal LDH and, haptoglobin, and indirect bilirubin levels at 3 consecutive visits Normalization of hematologic and hemolytic parameters
-Hgb concentration, reticulocyte count, and hemolytic markers, and change from baseline in these parameters through Week 16 of the double-blind period
-Hgb, reticulocyte count, and hemolytic markers, and change from baseline in these parameters through the study
Effect of nipocalimab on maintaining response in Hgb
-Proportion of participants who achieve the durable response in improvement of Hgb and maintain that response for up to 24 weeks throughout the study without the need of rescue therapy.
-Time to and duration of Hgb response
1.Time to response defined as the first time point at which the durable response criteria for the primary efficacy endpoint is met
2.Duration from the first time point at which the durable Hgb response criteria for the primary efficacy endpoint is met until the time point at which it is no longer met
-Change in the level of participant fatigue:
Change from baseline in the total score, item scores and impact and experience domains from the FACIT-Fatigue Scale through Week 24 of the double-blind period
-Changes in health-related quality of life parameters based on EQ -5D5L, SF -36, PGIS, and PGIC
-Impact of nipocalimab on corticosteroid use
Absolute reduction from baseline in average daily dose of prednisone or equivalent at Week 24 of the double-blind period among all participants The proportion of participants who achieve corticosteroid reduction to ≤ 7.5 mg/day of oral prednisone (or equivalent) at Week 24 of doubleblind period among participants on prednisone or equivalent >7.5 mg/day at baseline
The proportion of participants who achieve the durable response in improvement of Hgb during the double-blind period and maintain that response for up to 24 weeks throughout the study without the need of rescue therapy will be summarized descriptively. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The first of the three consecutive visits must be at or before week 16 in order to qualify for success in the primary efficacy endpoint. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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